Abstract Donor-specific alloantibodies (DSA) against HLA Class I and Class II are a major problem in organ transplantation. DSA can cause acute and chronic rejection and can be a major barrier to finding an acceptable donor when present pre-transplant in ?sensitized patients?. Unfortunately, no effective therapy exists to either deplete DSAs or block their effect. Our prior studies suggested that bone marrow (BM)-derived long-lived plasma cells (LLPCs) are a major source of persistent serum DSA. LLPCs are rare, poorly characterized and resistant to most current therapy in vivo. The mechanism of resistance to therapy may be due to the fact that LLPCs reside in pro-survival microenvironments/niches in which supporting stromal cells and leukocytes provide factors that enhance LLPCs longevity and prevent erstwhile apoptotic signals. Due to difficulties in procuring, isolating, and culturing human BM LLPCs, much of the biology of human PCs remains unclear and this has hindered the development of effective therapies. To overcome this problem, we developed an in vitro PC/stromal cell co-culture model. We now can maintain human PCs on mouse mesenchymal stromal cell (SC) lines in the presence of recombinant human IL-6. After 6 weeks culture, these PCs retain the typical PC phenotype and robustly secrete IgG and IgA Igs. Using this novel system, we now are poised to study functional BM-derived PCs in vitro and interrogate factors responsible for their longevity and antibody production.